): Prostate cancer is thought to initiate as non-invasive prostatic intraepithelial neoplasia (PIN), which progresses to locally invasive carcinoma, then to metastatic disease. The molecular genetic changes associated with prostate cancer progression are not completely understood. The broad goal of this proposal is to examine the role of the transcription factor Early Growth Response Gene 1 (Egr1) in the progression of prostate cancer from PIN to invasive carcinoma. Egr1 is highly expressed in prostate cancer, and its levels correlate with the tumor grade. Preliminary results show that Egr1 regulates the expression of multiple genes that enhance tumor progression in prostate cancer cells. Additionally, preliminary results from the study of Egr1 knockout mice show impaired prostate tumor progression. The hypotheses to be examined are: 1) that prostate cancer progression is delayed in transgenic mice lacking Egr1, and 2) that Egr1 induces the expression of genes that promote prostate cancer progression.
Three specific aims are proposed.
The first aim i s establish and characterize a transgenic mouse model for prostate cancer in the Egr1 null background. The Cr2-Tag mice, which develop prostate cancer as a result of the expression of the SV40 T antigen in the prostate, will be bred to Egr1/- mice to obtain Cr2-Tag/Egr1-/- and Cr2-Tag/Egr1 +/+ animals. We will monitor cancer progression in these mice by detailed histopathological analysis.
The second aim i s to determine the effect of Egr1 overexpression on the ability of prostate carcinoma cells to invade a reconstituted basement membrane. We will infect human prostate carcinoma cells with adenovirus overexpressing Egr1 and measure the ability of the cells to invade a reconstituted basement membrane matrix. The induced genes that are important for this process will also be determined.
The third aim i s to identify the genes that are differentially expressed in the prostate tumors of Egr1 knockout and wild type mice, by using high density oligonucleotide microarray hybridization analysis ("""""""" gene chip""""""""). The immediate goal is to train in a high-quality research environment and to develop tools and techniques that will prepare the Principal Investigator for a successful academic pathology career.
| Ehrig, T; Abdulkadir, S A; Dintzis, S M et al. (2001) Quantitative amplification of genomic DNA from histological tissue sections after staining with nuclear dyes and laser capture microdissection. J Mol Diagn 3:22-5 |
| Abdulkadir, S A; Carbone, J M; Naughton, C K et al. (2001) Frequent and early loss of the EGR1 corepressor NAB2 in human prostate carcinoma. Hum Pathol 32:935-9 |
| Abdulkadir, S A; Qu, Z; Garabedian, E et al. (2001) Impaired prostate tumorigenesis in Egr1-deficient mice. Nat Med 7:101-7 |
